title: High production rates sustain in vivo levels of PD-1high simian immunodeficiency virus-specific CD8 T cells in the face of rapid clearance.
abstract: Programmed Death 1 (PD-1) expression by human/simian immunodeficiency virus (HIV/SIV)-specific CD8 T cells has been associated with defective cytokine production and reduced in vitro proliferation capacity. However, the cellular mechanisms that sustain PD-1(high) virus-specific CD8 T cell responses during chronic infection are unknown. Here, we show that the PD-1(high) phenotype is associated with accelerated in vivo CD8 T cell turnover in SIV-infected rhesus macaques, especially within the SIV-specific CD8 T cell pool. Mathematical modeling of 5-bromo-2' deoxyuridine (BrdU) labeling dynamics demonstrated a significantly increased generation rate of PD-1(high) compared to PD-1(low) CD8 T cells in all memory compartments. Simultaneous analysis of Ki67 and BrdU kinetics revealed a complex in vivo turnover profile whereby only a small fraction of PD-1(high) cells, but virtually all PD-1(low) cells, returned to rest after activation. Similar kinetics operated in both chronic and acute SIV infection. Our data suggest that the persistence of PD-1(high) SIV-specific CD8 T cells in chronic infection is maintained in vivo by a mechanism involving high production coupled with a high disappearance rate.
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Rao
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Klatt
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Bastian R
authors.initials: BR
authors.lastname: Angermann
authors.forename: Zvi
authors.initials: Z
authors.lastname: Grossman
authors.forename: Derek C
authors.initials: DC
authors.lastname: Macallan
authors.forename: Martin
authors.initials: M
authors.lastname: Meier-Schellersheim
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000208:Acute Disease; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D049109:Cell Proliferation; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000472:pathogenicity*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000821:virology
chemical_list: D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor